This K99/R00 proposal seeks highly safe and efficient strategies to improve nicotine vaccine immunogenicity. Treatment of nicotine addiction remains an unmet medical need and nicotine vaccines evolve as a safe and effective therapy to treat nicotine addiction by induction of a relatively long-term abstinence rate with fewer side effects. Yet, only a small fraction of smokers respond to this therapy even after 5-7 monthly immunizations. Enhancing nicotine vaccine immunogenicity remains the key to increase the clinical response rate due to the positive correlation between serum anti-nicotine antibody (NicAb) titer and abstinence rate. An ablative fractional laser (AFL)-based, particulate vaccine and adjuvant-coated transdermal patch is proposed for nicotine vaccine delivery and adjuvantation. The AFL generates self-renewable microchannels (MCs) that provide free paths for vaccine delivery into the skin. Additionally, the AFL possesses superior ?built-in? adjuvant effects that are more potent than the majority of traditional adjuvants by induction of antigen presenting cell recruitment and long-term antigen depot. Encapsulation of nicotine vaccine and a safe cutaneous monophosphoryl lipid A (MPL) adjuvant into mixed poly(D,L-lactic-co-glycolic acid) (PLGA) particles with different sizes is expected to simulate a prime/boost immunization and induce the highest and prolonged NicAb titer and ?completely? block nicotine entry into the brain. The novel immunization is also expected to improve patient compliance by elimination of needle injection and induce an early-onset and long-lasting immune response. The novel immunization combines AFL, MPL adjuvant, and PLGA polymers already in the clinic to profoundly improve nicotine vaccine immunogenicity and is expected to gain FDA approval for clinical test if sufficient safety and efficacy data can be obtained from this study. Three specific aims are proposed: 1. Optimize AFL-based patch vaccine delivery, 2 & 3. Evaluate nicotine vaccine immunogenicity in mice (2) and miniature pigs (3). These aims will be achieved through courseworks at Harvard-MIT Division of Health Science and through multidisciplinary mentoring and collaboration with well-established scientists. This application fulfills one of the four major goals ?Treatment? and the objective ?To develop treatments for drug abuse and addiction in association with comorbid conditions? stated in 2010 NIDA strategic plan, and also addresses broad Challenge Area (15) Translational Science and specific Challenge Topic, 15-DA-101, Novel Approaches to Improve Immunogenicity of Vaccine against Small Molecules. The novel immunization strategy will have a broad impact on delivery and adjuvantation of not only nicotine vaccine, but also other anti- addiction vaccines (e.g., cocaine and heroin vaccines) under development and seasonal influenza vaccines in the clinic. Completion of this project will provide the candidate sufficient experience and a superior technology for transition to an independent researcher career in vaccine delivery and adjuvantation field.